Dietary cholesterol and saturated fatty acids raise LDL cholesterol levels and atherosclerotic cardiovascular disease risk. Due to the central role of the liver in regulating LDL cholesterol levels, the main purpose of this grant application is to study the influence of dietary cholesterol on liver gene expression and how this might relate to diet response of plasma lipoprotein levels. Although the importance of dietary saturated fat in regulating LDL cholesterol levels is recognized, for the purposes of this grant application it has been decided to make the problem more tractable by only studying the effects of dietary cholesterol. The experimental model to be used is the wild-type C57BI/6 mouse and induced mutant mice of the same genetic background. Dietary cholesterol regulation of mouse and human cholesterol 7a-hydroxylase (Cyp7a) will be studied using human Cyp7a natural flanking sequence transgenic mice. This will allow the role of this gene in dietary cholesterol regulation of lipoprotein levels to be assessed, and predict the importance of this gene for human dietary cholesterol response. The regulation, function, and possible role in diet response of CRSP, a novel dietary cholesterol regulated gene coding for a START-lipid binding domain protein recently discovered will also be studied. Finally, the identification of additional novel dietary cholesterol regulated genes and other genes determining differences in cholesterol metabolism and diet response between the sexes will be performed utilizing oligonucleotide microarrays,